Previous studies provide evidence that rare individuals remain seronegative and do not acquire HIV-1 infection despite multiple high-risk exposures to HIV-I. Polymorphisms in host genes may play critical roles in the apparent resistance to HIV-1 infection of these exposed seronegative (ES) individuals and in the variable rates of disease progression. However, the influence of some genetic polymorphisms associated with HIV-1 infection may be restricted to certain populations and not found in other ethnic groups. Furthermore, the effect of these alleles has been demonstrated inconsistently. In our preliminary studies of this proposal, the cohorts of ES, HIV-1 infected and HIV-1 seronegative individuals were investigated for such known polymorphisms including CCR5-A32, CCR5 promoter, CCR2-641, SDF-1-3'A, RANTES -403A and -28G. As reported by other groups, homozygous CCR5-A32 was associated with decreased chance of HIV-1 infection but no other known polymorphisms were found to be associated with the resistance to HIV-1 infection. In addition, polymorphisms of dendritic cell (DC)-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN) and its related homologue, DC-SIGNR were investigated. The homozygous DC-SIGNR 7/7 repeat was associated with an increased probability of HIV-1 infection, whereas the heterozygous 7/5 or homozygous 5/5 correlated with resistance to HIV-1 infection. The 5 repeat allele may act as a dominant resistance factor, while the 7 repeat allele may serve as a recessive risk factor for acquiring HIV-I. These findings suggest that the DC-SIGNR genetic polymorphisms may play a role in HIV-1 transmission. In this proposal, we will address these issues more rigorously in a larger population and investigate the mechanisms for the effect of DC-SIGNR genetic polymorphisms on HIV-1 transmission and disease progression by the following specific aims: 1) To determine the impact of DC-SIGNR polymorphisms on HIV-1 transmission, disease progression, and the HIV-1 pandemic at geographic sites (United States, Peru, China and South Africa); 2) To define the mechanisms for the effect of DC-SIGNR polymorphisms on HIV-1 transmission and disease progression by determining the expression and function of DC-SIGNR alleles. These studies should assist in the identification of new therapeutic targets and strategies to protect against HIV-1 transmission and control disease progression.